New Alkoxy Flavone Derivatives Targeting Caspases: Synthesis and Antitumor Activity Evaluation.

Joana Moreira,Hassan Bousbaa,Honorina Cidade,Andreia Palmeira,Diana Ribeiro,Madalena Monteiro,Madalena Pinto,Nair Nazareth,Lucília Saraiva,Patrícia Silva

doi:10.3390/molecules24010129

Abstract

The antitumor activity of natural flavonoids has been exhaustively reported. Previously it has been demonstrated that prenylation of flavonoids allows the discovery of new compounds with improved antitumor activity through the activation of caspase-7 activity. The synthesis of twenty-five flavonoids (4–28) with one or more alkyl side chains was carried out. The synthetic approach was based on the reaction with alkyl halide in alkaline medium by microwave (MW) irradiation. The in vitro cell growth inhibitory activity of synthesized compounds was investigated in three human tumor cell lines. Among the tested compounds, derivatives 6, 7, 9, 11, 13, 15, 17, and 18 revealed potent growth inhibitory activity (GI50 < 10 μM), being the growth inhibitory effect of compound 13 related with a pronounced caspase-7 activation on MCF-7 breast cancer cells and yeasts expressing human caspase-7. A quantitative structure-activity relationship (QSAR) model predicted that hydrophilicity, pattern of ring substitution/shape, and presence of partial negative charged atoms were the descriptors implied in the growth inhibitory effect of synthesized compounds. Docking studies on procaspase-7 allowed predicting the binding of compound 13 to the allosteric site of procaspase-7.

Highlights

IntroductionAt the core of the execution phase of apoptosis are the executioner caspases 3 and 7
Caspases are a family of proteases with a crucial role in the initiation and execution of apoptosis [1].At the core of the execution phase of apoptosis are the executioner caspases 3 and 7
Chrysin (3) as building blocks, according to the strategy illustrated in Scheme 1

Summary

Introduction

At the core of the execution phase of apoptosis are the executioner caspases 3 and 7 These proteases are stored as procaspases, which, after activation by proteolysis, cleave a large set of substrates leading to apoptosis. Baicalein (1), 3,7-dihydroxyflavone (2) and chrysin (3) have been reported as antitumor agents, by acting as inducers of apoptosis in human tumor cell lines through caspases-dependent pathways [4,5,6,7]. Our research group previously reported that the introduction of prenyl side chains on flavonoids scaffolds, including baicalein (1) and 3,7-dihydroxyflavone (2), was associated with an increase in their growth inhibitory activities towards several human tumor cell lines [8,9,10,11], being this effect related to the activation of caspase-7 for some of the prenylated derivatives [12].

Methods

Results

Conclusion